Propagation malfunctions due to gap junction dysregulation

Abstract

Gap junctions are membrane channels that connect the cytoplasm of adjacent cells allowing the cell-to-cell elec- trical coupling necessary for action potential propagation. Pathological conditions, such as malformations in connex- ins, mutations affecting phosphorylation of regulatory sites of connexins, alterations in gap junction organization, and type and quantity of connexin expression, can impede the normal electrical propagation. All these malfunctions can produce a dispersion of repolarization, implicated in ven- tricular arrhythmias. In fact, ventricular tachycardia and spontaneous ventricular arrhythmia occurred in more than twice as many connexin deficient hearts than wild-type hearts. We perform numerical simulations of a human ventric- ular model in order to mimic some of these pathological conditions. In particular, we consider a diminished Cx43 connexin expression, as well as altered connexin conduc- tance dynamics, i.e., modified maximum and minimum conductances gmax and gmin, half-inactivation voltage V1/2 and decay kinetics. Physiologically these modifica- tions can appear due to mutations or to different connexin configurations, i.e., forming heteromeric channels. Under these conditions we study the change in action potential duration (APD) and CV-restitution properties. We observe that, although CV diminishes with decreased connexin ex- pression, the APD remains almost constant up to the point of conduction block. Also, propagation differs for constant or time-dependent voltage conductance, conduction block occurring earlier for the former. While mutations result- ing in a stronger dependence of the delay time produced an appreciable change intercellular conductances, this ef- fect was not so important when the mutations affected the overall delay time. Thus, our results suggest that a correct description of gap junctional conductance is of big impor- tance for understanding action potential propagation un- der pathological conditions.